In general, it is known that cGMP, which is an intracellular second messenger, is decomposed and inactivated by phosphodiesterase which widely distributes in many tissues of the living body, and when said PDE activity is inactivated, the level of cGMP in cells is increased, and as a result, various pharmacological activities, for example, relaxation of vascular smooth muscle, relaxation of bronchial smooth muscle and inhibition of platelet aggregation are exhibited.
Moreover, it has been reported that such cGMP specific PDE inhibitors (i.e., PDE V inhibitors) are useful in the treatment of diseases caused by a functional disorder of cGMP-signaling, including hypertension, angina pectoris, myocardial infarction, chronic or acute heart failure, pulmonary hypertension, etc. (cf., WO 96/05176, etc.) and prostatic hyperplasia (Australian Patent Publication No. 9955977). It has also been reported that PDE V inhibitors may be useful in the treatment of female sexual dysfunction (Vemulapalli et al., Life Sciences, 67, 23–29 (2000)), diabetic gastroparesis (Watkins et al., J. Clin. Invest. 106: 373–384 (2000)), achalasia (Bortolotti et al., Gastroenterology; 118: 253–257 (2000)), diarrhea (Mule et al., Br. J. Pharmacol., 127, 514–520 (1999)), constipation (Bakre et al., J. Cell. Biochem. 77: 159–167 (2000)) and asthma (Turner et al., Br. J. Pharmacol., 111, 1198–1204 (1994)).
Furthermore, it has been also reported that 1-[4-ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenylsulfonyl]-4-methyl-piperazine [general name: Sildenafil] having PDE V inhibitory activity is useful in the treatment of diseases such as penile erectile dysfunction (copulative impotence), etc. (cf., Boolell et al., The Journal of Urology, Supplement, vol. 155, no. 5, p. 495A739 (1996); Terrett et al., Bioorganic & Medicinal Chemistry Letters, vol. 6, no. 15, p. 1819 (1996); and Ballard et al., British Journal of Pharmacology, Proceeding Supplement, vol. 118, p. 153 (1996)).
However, sildenafil has been reported to have side effects such as headache, facial flushing, gut disorder, rhinitis, color sense disorder, penile erectile continuance, etc. (Irwin et al., The New England Journal of Medicine, vol. 338, no. 20, p. 1397–1404 (1998); Morales et al., International Journal of Impotence Research, vol. 10, no. 2, p. 69–73 (1998); and Goldenberg, Clinical Therapeutics, vol. 20, no. 6, p. 1033–1048 (1998)).
In addition, sildenafil has also been reported that the effects of sildenafil on light response of retina tissues and its PDE VI inhibitory activity correlate each other in the experiments on dogs (Morales et al., International Journal of Impotence Research, vol. 10, no. 2, p. 69–73 (1998)), while it has been reported that PDE VI on retina plays an important role in the sensation of light (Morrales et al., International Journal of Impotence Research, vol. 10, no. 2, p. 69–73 (1998); Estrade et al., European Journal of Pharmacology, vol. 352, p. 157–163 (1998)).